In the developing world successes such as the eradication of smallpox have been balanced or outweighed by the new plagues. Infectious diseases cause nearly 25% of all human deaths (Table 4.1), rising to more than 50% in low income countries. Two billion people – one-third of the world’s population – are infected with tuberculosis (TB), up to 400 million people catch malaria every year and 200 million are infected with schistosomiasis. Some 500 million people are chronically infected with a hepatitis virus (either HBV or HCV) and 34 million people are living with HIV/AIDS, with 2.6 million new HIV infections in 2008 (65% in sub-Saharan Africa). Infections are often multiple and there is synergy both between different infections and between infection and other factors such as malnutrition. Many of the infectious diseases affecting developing countries are preventable or treatable, but continue to thrive owing to lack of money and political will.

Table 4.1 Worldwide mortality from infectious diseases

Disease	Estimated deaths (annual)
Acute lower respiratory infection	3.5 million
HIV/AIDS	2 million
Tuberculosis	2 million
Diarrhoeal disease	1.8 million
Malaria	1 million
Measles	350 000
Whooping cough	301 000
Tetanus	292 000
Meningitis	175 000
Leishmaniasis	51 000
Trypanosomiasis	10 000

The WHO has set eight Millennium Development Goals (MDGs), to be achieved by 2015: these include combating HIV/AIDS, malaria and other diseases. Currently, nine African and 29 non-African countries are on course to meet the malaria targets and the global incidence of TB is slowly falling. New HIV infections fell by 16% between 2000 and 2008 and antiretroviral treatment provision in low and middle income countries increased 10-fold between 2003 and 2008. A public/private partnership, the Global Fund, was established to combat AIDS, tuberculosis and malaria and has achieved much by providing the means for treatment for TB, insecticide-treated bed nets for malaria and antivirals for HIV. Several other funding streams (governmental, non-governmental and charitable) have also contributed to the fight against infection.

The impact of global warming on the spread of infection remains uncertain but may be significant. Both natural climatic events and the gradual global change in weather conditions can affect the spread and transmission of infectious diseases. Changes in temperature may directly influence the behaviour of insect vectors, while changes in rainfall may have an effect on water-borne disease. Climate change may also trigger population movement and migration, indirectly affecting infection transmission.

FURTHER READING

Byass P, Graham WJ. Grappling with uncertainties along the MDG trail. Lancet 2011; 378:1119–1120.

Infectious agents

The causative agents of infectious diseases can be divided into four groups:

Prions are the most recently recognized and the simplest infectious agents, consisting of a single protein molecule. They contain no nucleic acid and therefore no genetic information: their ability to propagate within a host relies on inducing the conversion of endogenous prion protein PrP^c into an abnormal protease-resistant isoform referred to as PrP^Sc.

Viruses contain both protein and nucleic acid and so carry the genetic information for their own reproduction. However, they lack the apparatus to replicate autonomously, relying instead on ‘hijacking’ the cellular machinery of the host. They are small (usually less than 250 nanometres (nm) in diameter) and each virus possesses only one species of nucleic acid (either RNA or DNA).

Bacteria are usually, though not always, larger than viruses. Unlike the latter they have both DNA and RNA, with the genome encoded by DNA. They are enclosed by a cell membrane and even bacteria which have adopted an intracellular existence remain enclosed within their own cell wall. Bacteria are capable of fully autonomous reproduction and the majority are not dependent on host cells.

Eukaryotes are the most sophisticated infectious organisms, displaying subcellular compartmentalization. Different cellular functions are restricted to specific organelles, e.g. photosynthesis takes place in the chloroplasts, DNA transcription in the nucleus and respiration in the mitochondria. Eukaryotic pathogens include unicellular protozoa, fungi (which can be unicellular or filamentous) and multicellular parasitic worms.

Other higher classes, notably the insects and the arachnids, also contain species which can parasitize man and cause disease: these are discussed in more detail on page 160.

Host–organism interactions

Each of us is colonized with huge numbers of microorganisms (10¹⁴ bacteria, plus viruses, fungi, protozoa and worms) with which we co-exist. The relationship with some of these organisms is symbiotic, in which both partners benefit, while others are commensals, living on the host without causing harm. Infection and illness may be due to these normally harmless commensals and symbiotes evading the body’s defences and penetrating into abnormal sites. Alternatively, disease may be caused by exposure to exogenous pathogenic organisms which are not part of our normal flora.

The symptoms and signs of infection are a result of the interaction between host and pathogen. In some cases, such as the early stages of influenza, symptoms are almost entirely due to killing of host cells by the invading organism. Usually, however, the harmful effects of infection are due to a combination of direct microbial pathogenicity and the body’s response to infection. In meningococcal septicaemia, for example, much of the tissue damage is caused by cytokines released in an attempt to fight the bacteria. The molecular mechanisms underlying host-pathogen interactions are discussed in more detail on page 78.

Sources of infection

The endogenous skin and bowel commensals can cause disease in the host, either because they have been transferred to an inappropriate site (e.g. bowel coliforms causing urinary tract infection) or because host immunity has been attenuated (e.g. candidiasis in an immunocompromised host). Many infections are acquired from other people, who may be symptomatic themselves or be asymptomatic carriers. Some bacteria, like the meningococcus, are common transient commensals, but cause invasive disease in a small minority of those colonized. Infection with other organisms, such as the hepatitis B virus, can be followed in some cases by an asymptomatic but potentially infectious carrier state.

Zoonoses are infections that can be transmitted from wild or domestic animals to man. Infection can be acquired in a number of ways: direct contact with the animal, ingestion of meat or animal products, contact with animal urine or faeces, aerosol inhalation, via an arthropod vector or by inoculation of saliva in a bite wound. Many zoonoses can also be transmitted from person to person. Some zoonoses are listed in Table 4.2.

Table 4.2 Zoonotic infections

Most microorganisms do not have a vertebrate or arthropod host but are free-living in the environment. The vast majority of these environmental organisms are non-pathogenic, but a few can cause human disease (Table 4.3). Person-to-person transmission of these infections is rare. Some parasites may have a stage of their life cycle which is environmental (e.g. the free-living larval stage of Strongyloides stercoralis and the hookworms), even though the adult worm requires a vertebrate host. Other pathogens can survive for periods in water or soil and be transmitted from host to host via this route (see below): these should not be confused with true environmental organisms.

Table 4.3 Environmental organisms which can cause human infection

Organism	Disease (most common presentations)
Bacteria
Burkholderia pseudomallei	Melioidosis
Burkholderia cepacia	Lung infection in cystic fibrosis
Pseudomonas spp.	Various
Legionella pneumophila	Legionnaires’ disease (pneumonia)
Bacillus cereus	Gastroenteritis
Listeria monocytogenes	Various
Clostridium tetani	Tetanus
Clostridium perfringens	Gangrene, septicaemia
Mycobacteria other than tuberculosis (MOTT)	Pulmonary infections
Fungi
Candida spp.	Local and disseminated infection
Cryptococcus neoformans	Meningitis, pulmonary infection
Histoplasma capsulatum	Pulmonary infection
Coccidioides immitis	Pulmonary infection
Mucor spp.	Mucormycosis (rhinocerebral, cutaneous)
Sporothrix schenckii	Lymphocutaneous sporotrichosis
Blastomyces dermatitidis	Pulmonary infection
Aspergillus fumigatus	Pulmonary infections

Routes of transmission

Endogenous infection

The body’s own endogenous flora can cause infection if the organism gains access to an inappropriate area of the body. This can happen by simple mechanical transfer, e.g. colonic bacteria entering the female urinary tract. The nonspecific host defences may be breached, for example, by cutting or scratching the skin and allowing surface commensals to gain access to deeper tissues; this is frequently the aetiology of cellulitis. There may be more serious defects in host immunity owing to disease or chemotherapy, allowing normally harmless skin and bowel flora to produce invasive disease.

Air-borne spread

Many respiratory tract pathogens are spread from person to person by aerosol or droplet transmission. Secretions containing the infectious agent are coughed, sneezed or breathed out and are then inhaled by a new victim. Some enteric viral infections may also be spread by aerosols of faeces or vomit. Environmental pathogens such as Legionella pneumophila and zoonoses such as psittacosis, are also acquired by aerosol inhalation, while rabies virus may be inhaled in the dust from bat droppings.

Faeco-oral spread

Transmission of organisms by the faeco-oral route can occur by direct transfer (usually in small children), by contamination of clothing or household items (usually in institutions or conditions of poor hygiene) or most commonly via contaminated food or water. Human and animal faecal pathogens can get into the food supply at any stage. Raw sewage is used as fertilizer in many parts of the world, contaminating growing vegetables and fruit. Poor personal hygiene can result in contamination during production, packaging, preparation, or serving of foodstuffs. In the western world, the centralization of food supply and increased processing of food has allowed the potential for relatively minor episodes of contamination to cause widely disseminated outbreaks of food-borne infection.

Water-borne faeco-oral spread is usually the result of inadequate access to clean water and safe sewage disposal and is common throughout the developing world. Worldwide, 1.1 billion people have no access to clean water and 2.6 billion do not have basic sanitation.

Vector-borne disease

Many tropical infections, including malaria, are spread from person to person or from animal to person by an arthropod vector. Vector-borne diseases are also found in temperate climates, but are relatively uncommon. In most cases part of the parasite life cycle takes place within the body of the arthropod and each parasite species requires a specific vector. Simple mechanical transfer of infective organisms from one host to another can occur, but is rare. Some vector-borne diseases are shown in Table 4.4.

Table 4.4 Infections transmitted by arthropod vectors

Vector	Disease	Microorganism
Mosquito	Malaria	Plasmodium spp.
	Lymphatic filariasis	Wuchereria bancrofti, Brugia malayi
	Yellow fever	Flavivirus
	West Nile fever	Flavivirus
	Dengue	Flavivirus
Sandfly	Leishmaniasis	Leishmania spp.
Blackfly	Onchocerciasis	Onchocerca volvulus
Tsetse fly	Sleeping sickness	Trypanosoma brucei
Flea	Plague	Yersinia pestis
	Endemic typhus	Rickettsia typhi
	Carrion’s disease	Bartonella bacilliformis
Reduviid bug	Chagas’ disease	Trypanosoma cruzi
Louse	Epidemic typhus	Rickettsia prowazekii
Louse	Louse-borne relapsing fever	Borrelia recurrentis
Hard tick	Lyme disease	Borrelia burgdorferi
	Typhus (spotted fever group)	Rickettsia spp.
	Babesiosis	Babesia spp.
	Tick-borne relapsing fever	Borrelia duttonii
	Tick-borne encephalitis	Flavivirus
	Congo-Crimean haemorrhagic fever	Nairovirus (Bunyavirus)

Direct person-to-person spread

Organisms can be passed on directly in a number of ways. Sexually transmitted infections are dealt with on page 160. Skin infections such as ringworm, and ectoparasites such as scabies and head lice, can be spread by simple skin-to-skin contact. Other organisms are passed on by blood- (or occasionally other body fluid) to-blood transmission. Blood-to-blood transmission can occur during sexual contact, from mother to infant either transplacentally or in the peripartum, between intravenous drug users sharing any part of their injecting equipment, when infected medical or other (e.g. tattoo needles) equipment is reused, if contaminated blood or blood products are transfused, or in any sporting or accidental contact when blood is spilled. Ingestion of infected breast milk is another route of person-to-person spread for some infections (e.g. HIV).

Direct inoculation

Infection can occur when pathogenic organisms breach the normal mechanical defences by direct inoculation. Some of the circumstances in which this can occur are covered under endogenous infection and blood-to-blood transmission above. Some environmental organisms may be inoculated by accident: this is a common mode of transmission of tetanus and certain fungal infections. Rabies virus may be inoculated by the bite of an infected animal.

Consumption of infected material

Although many food-related zoonotic infections are due to contamination of food with animal faeces (and are thus, strictly speaking, faeco-oral), several diseases are transmitted directly in animal products. These include some strains of Salmonella (eggs, chicken meat), brucellosis (unpasteurized milk) E. coli and the prion diseases kuru and vCJD (neural tissue).

Prevention and control

Methods of preventing infection depend upon the source and route of transmission, as described above.

Infection control measures. Poor infection control practice in hospitals and other healthcare environments can cause the transfer of infection from person to person. This may be air-borne, via fomites or a direct contact route. It is essential that all healthcare workers wash or clean their hands before and after patient contact and whenever necessary they should wear gloves, aprons and other protective equipment. This is particularly necessary when performing invasive procedures, or manipulating indwelling devices such as cannulae.

Five moments for hand hygiene.

Eradication of reservoir. In a few diseases, for which man is the only natural reservoir of infection, it may be possible to eliminate disease by an intensive programme of case finding, treatment and immunization. This has been achieved in the case of smallpox. If there is an animal or environmental reservoir, complete eradication is unlikely, but local control methods may decrease the risk of human infection (e.g. killing of rodents to control plague, leptospirosis and other diseases).

– For arthropod–vector-borne infections:

• destroying vector species (which may be practical in certain circumstances)

• taking measures to avoid being bitten (e.g. insect repellent sprays, impregnated bed nets).

– For food-borne infections. Improvements in food handling and preparation result in less contamination during processing, transport or preparation. Organisms intrinsically present in food can be killed by appropriate preparation and cooking. Improved surveillance and regulation of the food industry, as well as better health education for the public, is necessary.

– For faeco-oral infections. Improvements in water supply and sanitation (recognized in the Millennium Development Goals) could dramatically decrease the prevalence of faeco-oral infections.

Water collection.

– For blood-borne infections. Prevention of blood transfer, e.g. in blood transfusions and contaminated medical equipment. Donated blood is routinely tested for infection in most developed countries.

– For infections spread by air-borne and direct contact. Some air-borne-transmitted respiratory infections and some infections spread by direct contact can be controlled by isolating patients. This is often difficult, but isolation is useful in patients with severe immunodeficiency to protect them from infection.

Immunization (see p. 94).

Healthcare-associated infections (HCAI)

In recent years, the burden of morbidity, mortality and cost attributed to healthcare-associated infection has been highlighted in many developed countries. Although data from low income countries are lacking the impact of HCAI is likely to be even greater. Clostridium difficile, Staphylococcus aureus (especially MRSA), vancomycin-resistant enterococci and multiresistant Gram-negative organisms are all strongly associated with healthcare contact and are an increasing problem in hospitals worldwide. In the UK, the Department of Health estimates the risk of acquiring HCAI in a healthcare facility to be 6–10%, with HCAIs costing the NHS up to £1 billion per year. The response to HCAIs needs to be multifaceted. High standards of basic infection control (isolation, barrier precautions, hand hygiene and cleaning) need to be combined with decreased use of invasive devices such as vascular cannulae and urinary catheters, with better insertion and care standards when these are used. Antibiotic stewardship, with reduced overall usage and restriction of broad-spectrum agents, is essential to minimize antimicrobial resistance. There are already data to suggest that reduction in the use of cephalosporins has reduced the incidence of C. difficile. Often a combination of different methods can be used together to reduce a particular risk (e.g. ventilator-associated pneumonia): the so-called ‘care bundle’ approach.

FURTHER READING

Peleg AY, Hooper DC. Hospital-acquired infections due to gram-negative bacteria. N Engl J Med 2010; 362:1804–1813.

Classification of outbreaks

The type of outbreak has a bearing on public health measures that need to be instituted for its control.

Person to person where infection is passed from one infected individual to another and outbreaks of infection are separated by the incubation period.

‘Point source’ is where there is a single source of infection, e.g. food eaten at a social function. All those infected will develop symptoms at the same time, around the expected incubation period.

Common source where there is a single source of infection but over a period of time, e.g. a symptomatic carrier of infection working with food preparation. Many people will be exposed over a long period of time.

Epidemic. An increased unusual widespread infection in the community, causing waves of infection. These spread through communities and affect all people who have no active immunity to that infection.

Cases of some infectious diseases should be notified to the public health authorities so that they are aware of cases and outbreaks. Diseases that are notifiable in England and Wales are listed in Table 4.5.

Table 4.5 Diseases notifiable (to Local Authority Proper Officers) in England and Wales, under the Health Protection (Notification) Regulations 2010

Meningococcal septicaemia (without meningitis)

Viral haemorrhagic fever

Viral hepatitis

Whooping cough

Yellow fever

FURTHER READING

Cardo D, Dennehy PH, Halverson P et al. Moving toward elimination of healthcare-associated infections: a call to action. Am J Infect Control 2010; 38:671–675.

Chomel B, Belotto A, Meslin FX. Wildlife, exotic pets and emerging zoonoses. Emerg Infect Dis 2007; 13:6–11.

Horton R, Das P. Indian health: the path from crisis to progress. Lancet 2011; 377:181–183.

Relman DA. Microbial genomics and infectious diseases. N Engl J Med 2011; 365: 347–357.

Shurman EK. Global climate change and infectious disease. N Engl J Med 2010; 282:1061–1063.

SIGNIFICANT WEBSITES

Health Protection Agency: http://www.hpa.org.uk

WHO Infectious Diseases: http://www.who.int/topics/infectious_diseases/en/

Principles and basic mechanisms

Man constantly interacts with the world of microorganisms from birth to death. The majority cause no harm and some play a role in the normal functioning of the mouth, vagina and intestinal tract. However many microorganisms have the potential to produce disease. This may result from inoculation into damaged tissues, tissue invasion, a variety of virulence factors, or toxin production.

Specificity

Microorganisms are often highly specific with respect to the organ or tissue they infect (Fig. 4.1). For example, a number of viruses are hepatotropic, such as those responsible for hepatitis A, B, C and E and yellow fever. This predilection for specific sites in the body relates partly to the presence of appropriate receptors on different cell types and partly to the immediate environment in which the organism finds itself; e.g. anaerobic organisms colonize the anaerobic colon, whereas aerobic organisms are generally found in the mouth, pharynx and proximal intestinal tract. Other organisms that show selectivity include:

Streptococcus pneumoniae (respiratory tract)

Escherichia coli (urinary and alimentary tract).

Figure 4.1 Sites of infection with common organisms.

Even within a species of bacterium such as E. coli, there are clear differences between strains with regard to their ability to cause gastrointestinal disease (see p. 110), which in turn differ from uropathogenic E. coli responsible for urinary tract infection.

Within an organ a pathogen may show selectivity for a particular cell type. In the intestine, for example, rotavirus predominantly invades and destroys intestinal epithelial cells on the upper portion of the villus, whereas reovirus selectively enters the body through the specialized epithelial cells, known as M cells that cover the Peyer’s patches (see p. 262).

Pathogenesis

Figure 4.2 summarizes some of the steps that occur during the pathogenesis of infection. In addition, pathogens have developed a variety of mechanisms to evade host defences. For example, some pathogens produce toxins directed at phagocytes: Staphylococcus aureus (α-toxin), Streptococcus pyogenes (streptolysin) and Clostridium perfringens (α-toxin), while others such as Salmonella spp. and Listeria monocytogenes can survive within macrophages. Several pathogens possess a capsule that protects against complement activation (e.g. Strep. pneumoniae). Antigenic variation is an additional mechanism for evading host defences that is recognized in viruses (antigenic shift and drift in influenza), bacteria (flagella of salmonella and gonococcal pili) and protozoa (surface glycoprotein changes in Trypanosoma).

Figure 4.2 The pathogenesis of infection.

Epithelial attachment

Many bacteria attach to the epithelial substratum by specific organelles called pili (or fimbriae) that contain a surface lectin(s) – a protein or glycoprotein that recognizes specific sugar residues on the host cell. This family of molecules is known as adhesins (see p. 23). Following attachment, some bacteria, such as species of coagulase-negative staphylococci, produce an extracellular slime layer and recruit additional bacteria, which cluster together to form a biofilm. These biofilms can be difficult to eradicate and are a frequent cause of medical device-associated infections which affect prosthetic joints and heart valves as well as indwelling catheters. Many viruses and protozoa (e.g. Plasmodium spp., Entamoeba histolytica) attach to specific epithelial target-cell receptors. Other parasites such as hookworm have specific attachment organs (buccal plates) that firmly grip the intestinal epithelium.